In this dissertation, we explored the role of polyunsaturated fatty acid (PUFA) metabolites in neurodegeneration, Alzheimer's disease (AD), and aging, using Caenorhabditis elegans (C. elegans) as a model organism. Our investigation focused on the impact of cytochrome P450 (CYP)and epoxide hydrolase (EH) metabolic pathways on ferroptosis-mediated neurodegeneration, the relationship between oxylipins and AD pathology, and the influence of CYP-EH metabolites on lifespan, healthspan, and reproduction.We discovered that dihomo gamma linolenic acid (DGLA), a specific Ï⁹-6 PUFA, triggers ferroptosis-mediated neurodegeneration in dopaminergic neurons. This neurodegenerative effect occurs when DGLA is metabolized into dihydroxyeicosadienoic acid (DHED) via the action of CYP and EH enzymes. Our mechanistic study showed that it is the DHED metabolite that drives the neurodegenerative process, highlighting the critical role of CYP-EH-mediated PUFA metabolism in ferroptosis regulation. Consequently, this study identifies EH as a potential novel therapeutic target for addressing ferroptosis-related diseases and underscores the importance of understanding PUFA metabolism in the development of innovative treatment strategies.We further uncovered an intricate relationship between oxylipins, AÎø, and tau in neurodegeneration, demonstrating that AÎø and/or tau expression in C. elegans disrupts the oxylipin profile. EH inhibition alleviated the ensuing neurodegeneration, likely through elevating the epoxy-to-hydroxy ratio of various CYP-EH metabolites. This study established a link between AÎø and/or tau expression and CYP-EH metabolites, highlighting the potential therapeutic implications of epoxide hydrolase inhibition in AD.Lastly, we investigated the impact of pharmacological inhibition and genetic knock out of EH on the lifespan, healthspan, and reproductive capabilities of C. elegans and analyzed the corresponding alterations in oxylipin profiles. While the lifespan and reproduction remained unchanged in wild-type worms treated with the epoxide hydrolase inhibitor, AUDA, the genetic knockout of either ceeh-1 or ceeh-2 significantly shortened the lifespan and decreased egg production capacity. Although we identified significant changes in CYP-EH metabolites across experimental groups, the specific metabolites responsible for these effects remain elusive, mainly due to experimental challenges in testing a large number of compounds with possible synergistic effects during aging. Conventional techniques, such as agar plates, are limited by the difficulties in manual phenotypic and lifespan analyses, as well as in maintaining age-synchronized worms due to time-consuming progeny elimination processes. We discussed potential solutions, including high-throughput assays and microfluidic devices, to study the effect of numerous compounds on aging. However, we recognized that current techniques, like the use of 5-fluoro-2-deoxyuridine (FUDR) and PDMS-based microfluidic systems, present limitations that could interfere with the study of CYP-EH metabolites.Overall, this dissertation sheds light on the complex relationship between dietary PUFAs, their metabolites, and neurodegenerative diseases. It highlights the potential therapeutic value of targeting specific CYP-EH metabolites and sets the stage for future research in understanding their role in aging and neurodegeneration using the C. elegans model.
Read
